U.S. patent number 6,383,517 [Application Number 09/240,516] was granted by the patent office on 2002-05-07 for process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption.
This patent grant is currently assigned to Abbott Laboratories. Invention is credited to Kevin R. Engh, Yihong Qiu, Venkatramana M. Rao, Thomas L. Reiland.
United States Patent |
6,383,517 |
Qiu , et al. |
May 7, 2002 |
Process for preparing solid formulations of lipid-regulating agents
with enhanced dissolution and absorption
Abstract
A process for preparing a solid formulation of a
lipid-regulating agent comprising dissolving said lipid-regulating
agent particles in a surfactant solution, premixing an excipient,
wet granulating the mixture, drying the mixture and forming a
finished dosage form.
Inventors: |
Qiu; Yihong (Gurnee, IL),
Rao; Venkatramana M. (Lawrence, KS), Engh; Kevin R.
(Mundelein, IL), Reiland; Thomas L. (Gages Lake, IL) |
Assignee: |
Abbott Laboratories (Abbott
Park, IL)
|
Family
ID: |
22906851 |
Appl.
No.: |
09/240,516 |
Filed: |
January 29, 1999 |
Current U.S.
Class: |
424/464; 424/451;
424/452; 424/465; 514/772.3; 514/777; 514/778; 514/784 |
Current CPC
Class: |
A61K
9/1617 (20130101); A61K 9/1623 (20130101); A61K
9/1635 (20130101); A61K 9/1652 (20130101) |
Current International
Class: |
A61K
9/16 (20060101); A61K 009/20 (); A61K 009/48 () |
Field of
Search: |
;424/464,465,451,452,489 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0793958 |
|
Feb 1997 |
|
EP |
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8201649 |
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May 1982 |
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WO |
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Primary Examiner: Spear; James M.
Attorney, Agent or Firm: Rockey, Milnamow & Katz,
Ltd.
Claims
What is claimed is:
1. A process for preparing a solid formulation of a fibrate
comprising the steps of:
dissolving said fibrate in a surfactant solution;
premixing excipients;
mixing the excipient premix with the fibrate dissolved in
surfactant solution;
wet granulating the resulting fibrate/surfactant and excipient
mixture;
drying the mixture optionally in the presence of one or more
excipients,
and optionally forming a finished dosage form.
2. A process of claim 1 wherein the fibrate is fenofibrate.
3. A process of claim 1 where the mixture is dried by solvent
evaporation.
4. A process of claim 1 where the mixture is dried by fluid bed,
spinning disk drying or evaporation under reduced pressure.
5. A process of claim 1 where the surfactant is sodium
docusate.
6. A process of claim 1 further comprising forming a finished
dosage form.
7. A process of claim 6 where the finished dosage form is a
tablet.
8. A process of claim 6 where the finished dosage form is a
capsule.
9. The process of claim 1 wherein excipients are selected from the
group consisting of lacotse, starch, polyvinyl pryrrolidone and
magnesium stearate.
10. A process as in claim 1 where the mixture is granulated in a
fluidized bed or by means of a low shear or high shear mixer.
11. A composition prepared by the process of claim 1.
12. A composition prepared by the process of claim 2.
13. A method for treating hyperlipidemia comprising the
administration of a formulation prepared by the process of claim
1.
14. A method for treating of hyperlipidemia comprising the
administration of a formulation prepared by the process of claim 2.
Description
FIELD OF THE INVENTION
The present invention relates to a new process for preparing solid
formulations of lipid-regulating agents with enhanced dissolution
and absorption characteristics.
BACKGROUND OF THE INVENTION
2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,
1-methylethylester, also known as fenofibrate, is representative of
a broad class of compounds having pharmaceutical utility as
lipid-regulating agents. More specifically, this compound is part
of a lipid-regulating agent class of compounds commonly known as
fibrates, and is disclosed in U.S. Pat. No. 4,058,552.
Fenofibrate has been prepared in several different formulations,
c.f., U.S. Pat. Nos. 4,800,079 and 4,895,726. U.S. Pat. No.
4,895,726 discloses a co-micronized formulation of fenofibrate and
a solid surfactant.
U.S. Pat. No. 4,961,890 discloses a process for preparing a
controlled release formulation containing fenofibrate in an
intermediate layer in the form of crystalline microparticles
included within pores of an inert matrix. The formulation is
prepared by a process involving the sequential steps of dampening
said inert core with a solution based on said binder, then
projecting said fenofibrate microparticles in a single layer onto
said dampened core, and thereafter drying, before said solution
based on said binder dissolves said fenofibrate microparticles, and
repeating said three steps in sequence until said intermediate
layer is formed.
European Patent Application No. EP0793958A2 discloses a process for
producing a fenofibrate solid dosage form utilizing fenofibrate, a
surface active agent and polyvinyl pyrrolidone in which the
fenofibrate particles are mixed with a polyvinyl pyrrolidone
solution. The thus obtained mixture is granulated with an aqueous
solution of one or more surface active agents, and the granules
thus produced are dried.
PCT Publication No. W082/01649 discloses a fenofibrate formulation
having granules that are comprised of a neutral core that is a
mixture of saccharose and starch. The neutral core is covered with
a first layer of fenofibrate, admixed with an excipient and with a
second microporous outer layer of an edible polymer.
U.S. Pat. No. 5,645,856 discloses the use of a carrier for
hydrophobic drugs, including fenofibrate, and pharmaceutical
compositions based thereon. The carrier comprises a digestible oil
and a pharmaceutically-acceptable surfactant component for
dispersing the oil in vivo upon administration of the carrier,
which comprises a hydrophilic surfactant, said surfactant component
being such as not to substantially inhibit the in vivo lipolysis of
the digestible oil.
The prior art processes obtained small particles of fenofibrate by
the use of co-micronization steps. These resulting formulations may
not have maximized dissolution characteristics.
It is an object of the present invention to provide small particles
of lipid-regulating agents, more preferably fenofibrate, having
enhanced dissolution and absorption characteristics than those
particles of such agents prepared by the prior art techniques with
the need of micronizing the lipid-regulating agent.
SUMMARY OF THE INVENTION
The present invention is directed to a process for preparing a
solid formulation of a lipid-regulating agent with enhanced
dissolution and absorption characteristics.
This process comprises dissolving the lipid-regulating agent in a
surfactant solution, premixing an excipient, wet granulating the
lipid-regulating agent/surfactant solution and the premix, drying
the resulting mixture, and optionally sizing the dried granules and
forming a finished dosage form.
The mixture may be granulated by techniques well-known in the art,
preferably by a fluidized bed or by means of a low shear or high
shear mixer.
The finished oral dosage form may be prepared by techniques
well-known to those skilled in the art by sizing the mixture, dry
blending the resultant particles with excipients into the finished
oral dosage form, preferably as a tablet or capsule.
The formulation thus produced may be administered directly as a
granulated product, diluted into an appropriate vehicle for
administration, encapsulated into hard gelatin shells or capsules
for administration, or administered by other means obvious to those
skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the dissolution characteristics of a
representative composition prepared by the process of the present
invention and a prior art composition.
FIG. 2 is a graph showing the dissolution characteristics of
another representative composition prepared by the process of the
present invention and a prior art composition.
DETAILED DESCRIPTION OF THE INVENTION
The bulk lipid-regulating agent can be prepared by any available
method, as for example the compound fenofibrate may be prepared by
the procedure disclosed in U.S. Pat. No. 4,658,552, or the
procedure disclosed in U.S. Pat. No. 4,739,101, both herein
incorporated by reference.
The lipid-regulating agent is then dissolved in a surfactant
solution, such as for example, docusate sodium, in a solvent, such
as for example, acetone or methylene chloride, or a cosolvent such
as acetone-water in amounts ranging from 1 part by weight
surfactant solutions: 0.032 parts by weight fenofibrate to 1 part
by weight surfactant solutions: 1.16 parts by weight fenofibrate.
Other suitable surfactants include sorbitan esters, polysorbates,
lecithin, and all pharmaceutically-acceptable anionic, cationic,
ampholytic, nonionic surfactants. Other suitable solvents include
ethanol, methanol, ether, ethyl acetate, isopropyl alcohol, and
tetrahydofuran.
A premix of excipients is prepared. Suitable excipients include,
for example, lactose, starch, polyvinyl pyrrolidone, magnesium
stearate, or other pharmaceutically-acceptable excipients may be
used.
The lipid-regulating agent/surfactant solution and excipient premix
are then mixed together. The resulting mixture is then granulated,
for example, in a fluidized bed or a low or high shear mixer and
dried by well-known solvent evaporation techniques, as for example,
spray drying, fluid bed, spinning disk drying, or evaporation under
reduced pressure. The resultant material may then be sized, if
necessary and formulated into a finished dosage form, for example,
a tablet or capsule by conventional techniques such as direct
compression or other means.
The invention will be understood more clearly from the following
non-limiting representative examples:
EXAMPLE 1
Fenofibrate (12 g) and docusate sodium (3 g) were dissolved in 20
ml methylene chloride. Lactose anhydrous (32.5 g) and sodium starch
glycolate (2 g) were premixed. The premix was granulated with above
solution. The wet granules were tray dried in an oven at 40 C. The
dried granules were sieved through a 100 mesh screen and filled
into a hard gelatin capsule.
In vitro dissolution rate of the capsules were compared with that
of the reference, Lipanthyl, the marketed capsule product, which
contains the same amount of the active. USP apparatus II was used
for testing. The test conditions were: paddle speed=75 rpm;
dissolution medium=100 mM SDS solution; temperature=37 C.
Dissolution samples were analyzed by an HPLC method.
In vitro dissolution profiles of a capsule containing milled
fenofibrate, the reference capsule (Lipanthyl) and capsule from the
current invention are shown in FIG. 1. The data indicates that the
dissolution rate of the capsules of the present invention are
higher than the reference capsules. Based on U.S. Pat. No.
4,895,726, in vitro dissolution result can be correlated to the in
vivo absorption in humans. Thus, equivalent or increased
dissolution in vitro can result in bioavailability equivalent to or
improved over the reference in humans.
EXAMPLE 2
Fenofibrate (15 g) and docusate sodium (3 g) were dissolved in 45
ml acetone. Lactose anhydrous (29 g) and crospovidone (3 g) were
premixed. The premix was mixed with above solution. The wet mass
was tray dried in an oven at 30 C.
The dried solid was milled and sieved through a 100 mesh screen.
The small particles were filled into a hard gelatin capsule.
In vitro dissolution rate of the capsules were compared with that
of the reference, Lipanthyl, the marketed capsule product, which
contains the same amount of the active. USP apparatus II was used
for testing. The test conditions were: paddle speed=75 rpm;
dissolution medium=100 mM SDS solution; temperature=37 C.
Dissolution samples were analyzed by an HPLC method.
In vitro dissolution profiles of the reference capsules and
capsules from the present invention are shown in FIG. 2.
Preliminary data indicate that dissolution rate of the capsules of
the present invention are higher than the reference capsules. Based
on U.S. Pat. No. 4,895,726, in vitro dissolution result can be
correlated to the in vivo absorption in humans. Thus, equivalent or
increased dissolution in vitro can result in bioavailability
equivalent to or improved over the reference in humans.
* * * * *